4-(piperidin-1-yl)-2-butenoyl chloride；(E)-4-(piperidin-1-yl)but-2-enoyl chloride -Drug Synthesis Database

【结构式】

【分子编号】68473

【品名】4-(piperidin-1-yl)-2-butenoyl chloride；(E)-4-(piperidin-1-yl)but-2-enoyl chloride

【CA登记号】　

【分子式】C₉H₁₄ClNO

【分子量】187.669

【元素组成】C 57.6% H 7.52% Cl 18.89% N 7.46% O 8.53%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

Acetylation of the diarylamine (I) with Ac2O yields acetamide (II), which is reduced at the nitro group by means of H2 over Raney Ni in THF to give 6-aminoquinazoline derivative (III). Condensation of amine (III) with 4-(piperidin-1-yl)-2-butenoyl chloride (IV) in DMA affords the butenamide derivative (V), which is then deacetylated with NaOH, yielding anhydrous dacomitinib (VI). Finally, crude dacomitinib (VI) is recrystallized in dichloroethane/water .
Anhydrous dacomitinib (VI) can also be obtained as follows: Reduction of the 6-nitroquinazoline derivative (I) with H2 over Raney Ni in THF yields the 6-aminoquinazoline derivative (VII), which is then condensed with 4-bromo-2-butenoyl chloride (VIII) in the presence of Et3N in THF to give the 4-bromo-2-butenamide derivative (IX). Finally, 4-bromoamide (IX) is condensed with piperidine (X) using Et3N in DMA .
4-Bromo-2-butenoyl chloride (VIII) is obtained by hydrolysis of methyl 4-bromocrotonate (XI) with Ba(OH)2 in EtOH/H2O to produce acid (XII), which is finally treated with (COCl)2 in the presence of DMF in CH2Cl2 .
Anhydrous dacomitinib (VI) is also obtained by N-deprotection of its 3,4-dimethoxybenzyl derivative (XIII) with TFA in THF .

参考文献中间体

合成目标

【1】 Fakhoury, S.A., Lee, H.T., Reed, J.E., Schlosser, K.M., Sexton, K.E., Tecle, H., Winters, R.T. (Pfizer, Inc.). 4-Phenylamino-quinazolin-6-yl-amides. EP 1746999, JP 200753668, JP 2009007363, US 2005250761, US 7772243, WO 2005107758.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	68469	N-(3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine		C₁₅H₁₀ClFN₄O₃	详情	详情
(II)	68470	N-(3-chloro-4-fluorophenyl)-N-(7-methoxy-6-nitroquinazolin-4-yl)acetamide		C₁₇H₁₂ClFN₄O₄	详情	详情
(III)	68471	N-(6-amino-7-methoxyquinazolin-4-yl)-N-(3-chloro-4-fluorophenyl)acetamide		C₁₇H₁₄ClFN₄O₂	详情	详情
(IV)	68473	4-(piperidin-1-yl)-2-butenoyl chloride；(E)-4-(piperidin-1-yl)but-2-enoyl chloride		C₉H₁₄ClNO	详情	详情
(V)	68472	(E)-N-(4-(N-(3-chloro-4-fluorophenyl)acetamido)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide		C₂₆H₂₇ClFN₅O₃	详情	详情
(VI)	68474	(E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide	1110813-31-4	C₂₄H₂₅ClFN₅O₂	详情	详情
(VII)	68475	N⁴ -(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine		C₁₅H₁₂ClFN₄O	详情	详情
(VIII)	50564	(E)-4-bromo-2-butenoyl chloride		C₄H₄BrClO	详情	详情
(IX)	68476	(E)-N⁶-(5-bromopenta-1,3-dien-2-yl)-N4-(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine		C₂₀H₁₇BrClFN₄O	详情	详情
(X)	10158	Piperidine	110-89-4	C₅H₁₁N	详情	详情
(XI)	26358	methyl (E)-4-bromo-2-butenoate	1117-71-1	C₅H₇BrO₂	详情	详情
(XII)	50563	(E)-4-bromo-2-butenoic acid	13991-36-1	C₄H₅BrO₂	详情	详情
(XIII)	68477	(E)-N-(4-((3-chloro-4-fluorophenyl)(3,4-dimethoxybenzyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide		C₃₃H₃₅ClFN₅O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Compound (XIII) can be obtained by reductocondensation of 3-chloro-4-fluoroaniline (XIX) with 3,4-dimethoxybenzaldehyde (XXI) using NaCNBH3 or NaBH(OAc)3 in AcOH/i-PrOH to yield the benzylaniline derivative (XXII), which by condensation with 4-chloro-7-fluoro-6-nitroquinazoline (XVIII) in i-PrOH gives the tertiary amine (XXIII) . Substitution of fluoroquinazoline (XXIII) with NaOMe in refluxing MeOH affords the 7-methoxyquinazoline derivative (XXIV), which is reduced to the quinazoline-4,6-diamine (XXV) by means of H2 over Raney Ni in THF. Finally, compound (XXV) is coupled with 4-(piperidin-1-yl)-2-butenoyl chloride (IV) in DMA .
4-(Piperidin-1-yl)-2-butenoyl chloride (IV) can be prepared by condensation of methyl 4-bromocrotonate (XI) with piperidine (X) to yield methyl 4-(piperidin-1-yl)-2-butenoate (XXVI), which is then hydrolyzed with HCl to give 4-(piperidin-1-yl)-2-butenoic acid (XXVII). Finally, acid (XXVII) is reacted with (COCl)2 in the presence of DMF in CH2Cl2 .

参考文献中间体

合成目标

【1】 Fakhoury, S.A., Lee, H.T., Reed, J.E., Schlosser, K.M., Sexton, K.E., Tecle, H., Winters, R.T. (Pfizer, Inc.). 4-Phenylamino-quinazolin-6-yl-amides. EP 1746999, JP 200753668, JP 2009007363, US 2005250761, US 7772243, WO 2005107758.
【2】 Bridges, A.J., Horne, N.M., Jacks, T.E. et al. (Pfizer, Inc.). Preparation of substituted quinazolines. JP 2006517959, US 2004158065, WO 2004069791.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
（XXVI)	68482	(E)-methyl 4-(piperidin-1-yl)but-2-enoate		C₁₀H₁₇NO₂	详情	详情
(IV)	68473	4-(piperidin-1-yl)-2-butenoyl chloride；(E)-4-(piperidin-1-yl)but-2-enoyl chloride		C₉H₁₄ClNO	详情	详情
(X)	10158	Piperidine	110-89-4	C₅H₁₁N	详情	详情
(XI)	26358	methyl (E)-4-bromo-2-butenoate	1117-71-1	C₅H₇BrO₂	详情	详情
(XIII)	68477	(E)-N-(4-((3-chloro-4-fluorophenyl)(3,4-dimethoxybenzyl)amino)-7-methoxyquinazolin-6-yl)-4-(piperidin-1-yl)but-2-enamide		C₃₃H₃₅ClFN₅O₄	详情	详情
(XVIII)	19142	4-chloro-7-fluoro-6-nitroquinazoline		C₈H₃ClFN₃O₂	详情	详情
(XIX)	18688	3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline	367-21-5	C₆H₅ClFN	详情	详情
(XXI)	18304	3,4-Dimethoxybenzaldehyde; Veratraldehyde	120-14-9	C₉H₁₀O₃	详情	详情
(XXII)	68478	3-chloro-N-(3,4-dimethoxybenzyl)-4-fluoroaniline		C₁₅NClFO₂	详情	详情
(XXIII)	68479	N-(3-chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-6-fluoro-7-nitroquinazolin-4-amine		C₂₃H₁₇ClF₂N₄O₄	详情	详情
(XXIV)	68480	N-(3-chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-6-methoxy-7-nitroquinazolin-4-amine		C₂₄H₂₀ClFN₄O₅	详情	详情
(XXV)	68481	N⁴-(3-chloro-4-fluorophenyl)-N⁴-(3,4-dimethoxybenzyl)-6-methoxyquinazoline-4,7-diamine		C₂₄H₂₂ClFN₄O₃	详情	详情
(XXVII)	26709	(E)-4-(1-piperidinyl)-2-butenoic acid；(E)-4-(piperidin-1-yl)but-2-enoic acid		C₉H₁₅NO₂	详情	详情

Extended Information